The highly enantioselective Michael addition of ketones to nitrodienes catalyzed by the efficient organocatalyst system of pyrrolidinyl-thioimidazole and chiral thioureido acid

Article abstract of DOI:10.1039/c002197k

The highly enantioselective Michael addition reaction of ketones to nitrodienes was promoted efficiently by the accessible and fine-tunable organocatalytic system of pyrrolidinyl-thioimidazole and chiral thioureido acid. The corresponding adducts were afforded in good yields with high diastereoselectivities (up to 99:1) and excellent enantioselectivities (up to 99% ee). The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c002197k

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The highly enantioselective Michael addition of ketones to nitrodienes
catalyzed by the efficient organocatalyst system of pyrrolidinyl-thioimidazole
and chiral thioureido acid†
Zhao-Bo Li, Shu-Ping Luo, Yi Guo, Ai-Bao Xia and Dan-Qian Xu*
Received 4th February 2010, Accepted 14th April 2010
First published as an Advance Article on the web 22nd April 2010
DOI: 10.1039/c002197k
The highly enantioselective Michael addition reaction of
ketones to nitrodienes was promoted efficiently by the acces-
sible and fine-tunable organocatalytic system of pyrrolidinyl-
thioimidazole and chiral thioureido acid. The corresponding
adducts were afforded in good yields with high diastereose-
lectivities (up to 99 : 1) and excellent enantioselectivities (up
to 99% ee).
Pyrrolidinyl-thioimidazole 1 (Fig. 1) and its analogs were
designed in our previous work and successfully applied to cat-
alyze some asymmetric reactions5 including the Michael addition
of ketones to nitroolefins. Moreover we developed the chiral
thioureido acids 2a–7b used as novel chiral functional acidic
additives for the organocatalyst 1, and the readily available
and fine-tunable organocatalytic system display well catalytic
activity and excellent enantioselectivity.5c To explore further
application of the pyrrolidinyl-thioimidazole and chiral thioureido
acid organocatalytic system, the asymmetric Michael addition of
ketones to nitrodienes was investigated.
Introduction
As one of the most important chiral carbon–carbon bond-
forming processes in modern organic chemistry, the asymmetric
catalytic Michael addition employing chiral organocatalysts has
gained more and more attention.1,2 Among them, the asymmetric
conjugate additions of aldehydes or ketones to Michael accepters,
such as a,b-unsaturated carbonyl compounds, nitroolefins, phos-
phonates, vinylic sulfones and acrylonitriles have been developed
through enamine activation mode.2 In particular, as one of the
most efficient, atom-economical and powerful methods, the direct
Michael reaction of carbonyl compounds to nitroolefins has
stimulated extensive interest because the enantioenriched adducts
(g -nitrocarbonyl compounds) serve as versatile intermediates for
the preparation of complex organic targets and thus considerable
attention has been given to developing efficient catalytic systems
for a wide variety of carbonyl compounds as carbon nucleophiles.3
In contrast, only b-nitrostyrenes were most widely used and
little progress has been made in the development of nitrodienes
as Michael acceptors. Recently Alexakis group succeeded in
developing the asymmetric organocatalyzed Michael addition of
aldehydes to nitrodienes.4 Whereas, the development of efficient
organocatalysts for the Michael addition of ketones to nitrodienes
is still challenging (Scheme 1).
Fig. 1 Pyrrolidinyl-thioimidazole and chiral thioureido acids.
Results and discussion
Preliminary experiments were carried out in order to examine
the reactivity in the direct Michael addition. Cyclohexanone
8a and ((1E,3E)-4-nitrobuta-1,3-dienyl)benzene 9a were used as
model substrates in the presence of pyrrolidinyl-thioimidazole
1 and the thioureido acid 2a. The desired 1,4-addition adduct
was obtained and significant solvent effects were noted. As the
results summarized in Table 1, polar solvents and protonic solvents
seemed to suppress the reaction and only medium yields, low
diastereo- and enantioselectivities were obtained (entries 1–5).
This indicated that polar solvents may interact with 2a through
hydrogen bonding to weaken the activation ability of 2a towards
the reaction. Aliphatic ethers were not good solvents for this
reaction either because of the poor solubility of the catalyst system
(entries 9 and 10). While in halohydrocarbon solvents, such as
dichloroethane, chloroform, and 1,2-dichloroethane (DCE) both
Scheme 1 The Michael addition of nitrodienes.
State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technol-
ogy, Zhejiang University of Technology, Hangzhou, China. E-mail: chrc@
zjut.edu.cn; Fax: +86-571-88320066; Tel: +86-571-88320066
† Electronic supplementary information (ESI) available: Proton and
Carbon NMR spectra, HPLC Analysis Spectra. CCDC reference number
744505. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c002197k
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Table 1 Solvent screen for the direct Michael addition of 8a to 9aa
Table 2 The effect of different thioureido acids on the Michael reaction
of 8a to 9a catalyzed by 1a
Entry Solvent
Time (d) Conv. b(%) dr c(syn/anti) ee d(%)
Entry Additive acid Time (d) Conv. b(%) dr c(syn/anti) ee d(%)
1
2
DMSO
DMF
3
3
3
3
3
2
2
2
3
3
68
69
53
50
55
97
98
99
69
36
68 : 32
61 : 39
63 : 37
59 : 41
64 : 36
79 : 21
78 : 22
78 : 22
62 : 38
67 : 33
58
53
32
-14
16
70
70
74
48
57
1
—
3
3
2
2
2
2
2
2
2
2
2
2
2
2
1
3
53
60
99
97
99
97
99
99
98
99
99
99
97
98
96
80
75 : 25
73 : 27
78 : 22
79 : 21
92 : 8
51
68
74
75
88
81
90
85
89
81
99
83
87
84
99
99
3
4
5
6
CH3OH
2
3
4
5
6
7
8
9
10
11
12
13
14
15e
16f
PhCOOH
i-PrOH
2a
2b
3a
3b
4a
4b
5a
5b
6a
6b
7a
7b
6a
6a
n-BuOH
CH2Cl2
7
8
9
CHCl3
90 : 10
95 : 5
90 : 10
95 : 5
91 : 9
98 : 2
ClCH2CH2Cl
C2H5OC2H5
Me2CHOCHMe2
10
a A mixture of cyclohexanone (0.25 mmol), phenylnitrodiene (0.25 mmol)
and catalyst system 1/2a (10 mol% each) in different solvents was stirred
at room temperature for the time given in tables. b Determined by GC.
c Determined by GC-MS. d Determined by chiral HPLC analysis (Daicel
Chiralpak AD-H, hexane/i-PrOH = 90 : 10, flow rate 1.0 mL min-1, l =
264 nm).
93 : 7
89 : 11
85 : 15
98 : 2
98 : 2
a A mixture of cyclohexanone (0.25 mmol), phenylnitrodiene (0.25 mmol)
and catalyst system (10 mol% each) in DCE was stirred at room
temperature for the time given in tables. b Determined by GC. c Determined
by GC-MS. d Determined by chiral HPLC analysis (Daicel Chiralpak AD-
H, hexane/i-PrOH = 90 : 10, flow rate 1.0 mL min-1, l = 264 nm). e 5 mol%
catalyst system was loaded. f 3 mol% catalyst system was loaded.
yields and enantioselectivities were good (entries 6–8). DCE was
found to be the best solvent, which afforded 10a with high yield
of 99%, with moderate diastereo- and enantioselectivity of 78 : 22
and 74% respectively within two days.
Next, in order to accomplish higher enantioselectivity, we care-
fully fine-tuned the structure of chiral thioreido acids according to
its synergistical effects6 and steric effects of the chiral thioureido
acids. As shown in Table 2, without acidic addictive (entry 1)
or used the benzoic acid (entry 2), the pyrrolidinyl-thioimidazole
1 failed to generate the desired product in good yields and ee
values. In contrast, all Michael reactions catalyzed by 1 and
thioureido acids proceeded well and the product were obtained
with the yields higher than 96%, with the ee values ranging
from 74% to 99% (entries 3–15). Moreover, R2 groups of chiral
thioureido acids was benzyl, phenyl or tert-butyl group (entries
5–15) showed better steric efficiency than 2a and 2b (entries 3 and
4). As the phenomena found in the Michael reaction of ketones to
nitroolefins,5c the configuration of the chiral thioureido acids had
important influence on the reaction performance, especially on
the enantioselectivity of the product. The chiral thioureido acids
3a, 4a, 5a, 6a and 7a, all having an R configuration (entries 5,
7, 9, 11 and 13), showed better efficiency than 3b, 4b, 5b, 6b and
7b which have an S configuration (entries 6, 8, 10, 12 and 14).
All these results indicated that the chiral thioureido acids could
act in a dual role, not only activating pyrrolidinyl-thioimidazole 1
presumably by providing a proton, but also activating and chirally
inducing the phenylnitrodiene 9a by hydrogen bonding and steric
effects. To our delight, no significant decrease of both yield and ee
value was detected even when the amount of the catalyst system
of 1/6a was reduced to 5 mol% (entries 15 and 16).
tetrahydropyran-4-one were very suitable substrates, giving the
products with the isolated yields of 82% to 93% and ee values
of 85% to 99% (entries 1, 3, 4, 7, 9, 10, 13, 15 and 16). When cy-
clopentanone and 1-methylpiperidin-4-one were as Michael donor
substrates, the enantioselectivities of corresponding products were
decreased. Although the diastereoselectivity was mild decline, 4-
tert-butyl cyclohexanone was also a suitable substrate for the
Michael addition reaction, leading to the products with the ee
values of up to 96% (entries 5, 11 and 17). Aliphatic ketone and
aldehydes were also tested and moderate to good results were
obtained (entries 19–21).
To explain the origin of the high enantioselectivity performance
of the synergistic co-catalytic system 1/6a for the Michael
addition reactions, a transition state model is proposed and the
absolute configuration of adduct 10m was confirmed by an X-ray
crystallographic analysis (Fig. 2). Because of the ionic interaction
of the pyrrolidinyl-thioimidazole and the carboxylate of the chiral
thioureido acid, the stable ammonium catalyst ionic pair is formed;
therein the chiral thioureido acids with the R configuration can
synergistically cover the up-side of the phenylnitrodiene 9a with
1 more efficiently than those chiral thioureido acids with the
S configuration. Because of the combined steric effects of the
thioimidazole group of 1 and the chiral phenyl group of 6a,
the Si face of phenylnitrodiene 9a was shielded efficiently and
the enamine which was activated by the pyrrolidine motif of 1
is favored to attack the phenylnitrodiene 9a which was activated
by 6a through hydrogen bonding from the Re face to afford the
desired (S,S) adduct.
With the optimal reaction conditions established, the Michael
addition reactions with a variety of cyclo-ketones, aliphatic ketone
and aldehydes to nitrodienes were explored. As the results in
Table 3 showed, cyclohexanone, tetrahydrothiopyran-4-one and
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Table 3 Michael addition reactions of cyclo-ketones, aliphatic ketone and aldehydes to nitrodienesa
Entry
8/X
9/R¢
Time/h
Product
Yield b(%)
dr c(syn/anti)
ee d(%)
1
2
3
4
5
6
7
8
8a/CH2
9a/H
24
24
24
24
24
24
36
36
36
36
36
36
18
18
18
18
18
18
48
20
20
10a
10b
10c
10d
10e
10f
10g
10h
10i
92
87
84
85
92
91
90
84
82
84
89
89
93
91
89
89
93
93
82
76
77
98 : 2
95 : 5
99
95
97
96
96
72
85
93
93
95
93
77
87
91
93
94
93
73
80
83
68
8b/(CH2)0
8c/O
9a/H
9a/H
89 : 11
99 : 1
8d/S
9a/H
8e/CH t-Bu
8f/NCH3
8a/CH2
9a/H
83 : 17e
98 : 2
9a/H
9b/OMe
9b/OMe
9b/OMe
9b/OMe
9b/OMe
9b/OMe
9c/Cl
99 : 1
8b/(CH2)0
8c/O
8d/S
8e/CH t-Bu
8f/NCH3
8a/CH2
8b/(CH2)0
8c/O
8d/S
8e/CH t-Bu
8f/NCH3
3-Pentanone
Isovaleraldehyde
Isobutyraldehyde
90 : 10
89 : 11
91 : 9
9
10
11
12
13
14
15
16
17
18
19
20
21
10j
10k
10l
89 : 11e
98 : 2
10m
10n
10o
10p
10q
10r
10s
10t
10u
99 : 1
97 : 3
9c/Cl
9c/Cl
88 : 12
93 : 7
9c/Cl
9c/Cl
88 : 12e
72 : 28
97 : 3
9c/Cl
9a/H
9a/H
59 : 41
64 : 36
9a/H
a A mixture of cyclo-ketones or aliphatic ketone and aldehydes (0.25 mmol), nitrodienes (0.25 mmol) and catalyst system 1/6a (5 mol% each) in DCE was
stirred at room temperature for the time given in tables. b Isolated yield. c Determined by GC-MS. d Determined by chiral HPLC analysis (Daicel Chiralpak
AD-H, hexane/i-PrOH = 90 : 10, flow rate 1.0 mL min-1). The configurations of 10a–10s were assumed by analogy to 10m and the configurations of
10t–10u were assumed by analogy to corresponding products in Ref.4 e This ratio referred to two syn-products with S configuration to those with R
configuration in the 4-position of cyclohexanone (See ESI and Ref.7).
asymmetric Michael addition reactions. The Michael adducts
were afforded with good isolated yields (up to 93%), high
diastereoselectivities (up to 99 : 1) and excellent enantioselectivities
(up to 99% ee). Further applications of this organocatalytic system
were ongoing in our laboratory.
Acknowledgements
The authors acknowledge the National Natural Science Founda-
tion of China for the financial support (NSFC 20772110).
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